Automated liquid handling systems are designed to aspirate or dispense minute, accurate quantities of liquid for the purpose of transferring liquid from one reservoir to another. The systems are configured to aspirate liquid from and dispense liquid to standardized liquid reservoirs known as wellplates, which are configured to hold biological or chemical samples, usually suspended in a neutral liquid medium. Liquid handling systems comprise a dispensing head having one or more fluid pathways through which is controlled the dispensing of the liquid and a support surface for holding the wellplates in proximity to the dispensing head. The dispensing head and/or the support surface are configured to move relative to each other in at least one or more dimensions to facilitate dispensing and transfer of wellplates through the dispensing area.
The fluid pathways of the dispensing head are pressurizable to control the flow of liquids being handled. The fluid pathways may be in communication with an external source of pressure or may be configured to have individual pumping capability such as by having individual pumping chambers integrated therein. In one example of a liquid handling system, the pumping chambers may be defined by an array of syringe bodies that are operated in unison by the system to aspirate and dispense liquid through an array of multiple dispensing tips or cannulas in fluid communication with the syringe bodies. The cannula array corresponds to the number and arrangement of syringe bodies. The liquid handling system is operated by moving the dispensing head to a source wellplate, lowering the cannulas into liquid contained in the wells and operating the syringes to aspirate liquid into the cannula tips. The dispensing head then is repositioned over a destination wellplate, the cannulas lowered into the wells and liquid dispensed. An advantage offered by automated liquid handling systems is an increase in efficiency offered by the simultaneous operation of multiple cannulas versus manual liquid sample handling conducted by lab technicians using single pipettes to fill or aspirate samples from individual wells.
Automated liquid handling systems are useful in the biotechnology and pharmaceutical industries where numerous organic samples must be mixed and stored during their testing. Such testing is especially cumbersome in research involving proteins in which numerous samples are mixed in a biologically compatible solution, such as Dimethyl Sulfoxide (DMSO). By providing an automated way to dispense a common liquid into a plurality of sample wells, the liquid handling system greatly reduces the amount of time and labor needed to accomplish large scale testing of the various organic compounds. In automating the operation of a liquid handling system, provisions may be made to dispense liquid into multiple wellplates without requiring human intervention to place and align the plates in the path of the dispensing head of the system. Reducing the amount of human intervention necessary between wellplate preparations is significant due to the high number of sample preparations required in the scientific evaluation of various experimental compounds.
Various improvements have been made to automated liquid handling systems to increase the number of samples that may be prepared before human intervention is required to reload or reset the equipment. First, the number of sample wells defined on a single wellplate and corresponding cannulas have increased. Industry standards for the numbers of wells in a wellplate have increased over the years from 4 to 96 to 384 to 1,536 well systems. The dimensions of the wellplates remains the same standardized size despite the increase in the number of wells per plate, requiring that the volume of each well be decreased accordingly and arrangement density be increased. In addition, dispensing heads can be configured to have a removable cannula array that can be reconfigured so that different size wellplates (96, 384, 1536) can be more efficiently serviced by the liquid handling system by simply changing the cannula array to a different configuration. However, although the efficiency in the number of samples increases by increasing the array size, problems in dealing with clogging and misdispensing also become more complicated as the array size and density increase.
Clogging of one or more of the cannulas, though may be detectable by computer software of the dispenser controller monitoring the syringe bodies, still can be difficult to correct in a large array system. Removal of and replacement of a cannula array can introduce fluid pathway sealing problems or misalignment of the array that can cause the cannulas to “crash” into a wellplate when it is lowered if the cannulas miss their intended wells. Additionally, in systems that use disposable plastic tips in place of cannulas, expensive replacement tips must be maintained on hand for such service of the arrays. If the cannula array is bolted to the syringe body platform of the dispensing head, the task of aligning the array can become a difficult, time-consuming job requiring a high degree of operator skill to achieve proper alignment.
A useful operation performed by the liquid handlers described above is plate reformatting of wellplates containing existing samples to new wellplates having a higher well density to reduce the space required to store samples. Samples stored in wellplates having 96 wells may be aspirated and transferred by the dispensing head to wellplates having 384 or 1536 wells per plate. In this manner, samples previously contained on several low-density source plates can be combined onto a single high-density destination plate, easing storage requirements for the laboratory. Accordingly, as laboratories strive to maximize the efficiency with which sample storage space is used, a common task that must be performed is reformatting of existing source wellplates to higher density wellplates to more efficiently store and process the samples. Due to the numerous compounds that need to be tested in biological experiments, sample mixing and reformatting procedures are run for extensive periods without interruption in order to keep up with the demand for sample preparation and maintenance.
Currently liquid handling devices are available that are configured to permit reconfiguration of the cannula array. The CyBio CyBi-Well 384/1536 liquid handler available from CyBio AG, Goschwitzer STR. 40, DD7745, Jena, Germany (also available as the Matrix PlateMate 96/384 automated pipette) is configured to provide a removable dispensing head unit that may be interchanged with head units of different cannula array configurations. The head is removably maintained in place by brackets that engage the head unit and are movable by an electric solenoid to lock the head in place during use. However, the dispensing head of the CyBio device does not permit changing only the cannula configuration, but also requires that the syringe body array also be changed with the head unit if the format is to be changed. Additionally, the Cybio device is not fully automated. An operator must load and unload the head units after being unclamped from the device. Additionally, the operator must peel-away a disposable gasket material that overlies the multiple plastic cannulas that serve as dispensing tips. The gasket material must be reapplied when reinstalling the head unit.
A dispensing head having an interchangeable cannula array is desirable for other reasons in addition to facilitating reformatting procedures. If small quantities of liquid are to be dispensed into high-density wellplates, shorter, smaller diameter cannulas are preferably fitted to the dispensing head. The shorter, smaller diameter cannulas are desirable because the smaller volume they define facilitates accurate metering of minute quantities of liquid. Also the smaller cannula tips are easier to align with the high-density wellplate. Another situation that may require changing the cannulas of the dispensing system arises when clogging in one or more of the cannulas is detected. Also, it may be necessary to change the cannula array if cross-contamination of any of the cannula tips by the sample liquids has occurred.
The capacity of a liquid handling system may also be increased by automating the movement of the dispensing head relative to the wellplates. Automating movement can be accomplished by either imparting a movement mechanism to the dispensing head, or to the support surface for a plurality of wellplates or to both. Liquid handling systems that employ an automated movable support surface to move multiple wellplates into position under the dispensing head are available in the CyBio device mentioned above and also in the Zymark SciClone FD series liquid handler. Both provide a movable support surface to transfer wellplates beneath the dispensing head in addition to providing dispensing head movement. The systems provide automated movement of the support surface along a single axis of movement. Additional robotic components may be added to the system that can transfer a series of wellplates from an adjacent storage location, such as a stacking tower, to the movable support surface then retrieve wellplates from the support surface that have been processed and return them to the storage location.
Independent movement of the dispensing head by robotic actuators provides displacement relative to the sample support surface necessary to reach multiple wellplates. The CyBio device provides a system capable of movement in two dimensions. However, the Zymark SciClone and another liquid handling device available under the trade name Biomek FX available from Beckman Coulter of 4300 North Harbor Boulevard, Fullerton, Calif., provide liquid handling systems with dispensing head movement in three dimensions. Three-dimensional movement of the dispensing head provides greater range of motion and positional accuracy.
To aid in the processing of samples by liquid handling systems, it would be desirable to provide a system capable of automatically accessing wellplates from different locations and capable of automatically changing the cannula array format of the dispensing head with minimal or no human assistance. Also, to take advantage of a reconfigurable array system and to facilitate servicing of the cannulas, it would be desirable to provide a quick-release cannula array mounting system that permits a user to quickly change a cannula array while insuring its proper alignment with the fluid pathway of the dispensing head and the wellplates that are to be serviced by the array. An object of the present invention is to provide such a system.